Several paths of evidence converge in implicating a role for the cholinergic system in the pathophysiology of affective illness. In both unipolar depressed and euthymic bipolar subjects, cholinomimetic drugs (i.e., muscarinic agonists, acetylcholinesterase inhibitors) exacerbate depressive signs and symptoms such as dysphoria, psychomotor retardation, impairment of attention and memory, hypothalamic pituitary adrenal axis hyperactivity and sleep EEG abnormalities. In healthy subjects, the acetylcholinesterase inhibitor physostigmine elicits a range of depressive symptoms including dysphoria, anergia, psychomotor slowing, emotional lability, sleep disturbances, memory and concentration impairment, and with higher doses, tearfulness and depression. These effects have been shown to reflect stimulation of muscarinic receptors. Cholinomimetics also exacerbate behavioral despair in putative animal models of depression. Conversely, the anticholinergic agent biperidine improved symptoms of depression in a placebo controlled study. Moreover, muscarinic cholinomimetics and a choline rich nutrient, lecithin (phosphatidylcholine) exert antimanic effects in bipolar subjects. Potentially consistent with these observations, depressed subjects exhibit hypersensitivity to cholinomimetic agents. Administration of muscarinic cholinergic agonists, ACh releasing agents or acetylcholinesterase inhibitors induce exaggerated effects on REM density and latency in depressed subjects than in healthy controls. In addition, both manic and depressed bipolar subjects show increased pupillary sensitivity to the muscarinic cholinergic agonist pilocarpine relative to controls. Despite the data implicating the mAChR receptor system in mood disorders, no direct in vivo investigations of the central mAChR have been performed in depressed subjects. A novel PET radioligand, [18F]FP-TZTP was recently developed by Eckelman (2001a; b) as a selective agonist of M2 receptors. Because the M2 receptor functions predominantly as a presynaptic release-controlling autoreceptor, decreased distribution volume (V) of this receptor could conceivably give rise to increased postsynaptic muscarinic receptor sensitivity. This application proposes a pilot PET study of M2 receptor distribution volume in currently depressed subjects with major depressive disorder (n=15), currently depressed subjects with bipolar disorder (n=15), and psychiatrically healthy controls (n=15). The proposed pilot study will test the central hypothesis that M2 receptor V is decreased in regions where they are primarily located presynaptically in depressed subjects relative to healthy controls. The proposed study will advance knowledge regarding the pathophysiology of depression. During the past one year, about 14 depressed subjects and 9 controls have been imaged. The analysis has been completed for these subjects. The data show a trend toward decreased cholinergic receptor binding in the depressed subjects in the amygdala and several other structures. Establishing the statistical significance of these abnormalitities requires testing in larger groups of subjects, so data collection in additional subjects is in progress.